A new study has found that the immune remodeling associated with fasting can be recapitulated by activating a subset of neurons in the hypothalamus. The findings could be important in the context of fasting mimicking, metabolic disorders, and cancer [1].
Fasting and the immune system
Decades after the modern field of geroscience was born, caloric restriction still holds the crown as the very first and arguably still the most effective intervention. While fasting, a form of caloric restriction, offers numerous benefits [2], there are also many caveats and the practice should be undertaken with caution. For instance, several recent studies tie intermittent fasting to a higher risk of cardiovascular mortality [3].
Fasting can have a profound effect on the immune system. It is known to lower inflammation and reduce the number of circulating pro-inflammatory monocytes – marrow-derived cells that can infiltrate tissue and become macrophages or dendritic cells, part of the innate immune system. However, the mechanisms that drive this immune reorganization are not entirely understood.
In this new study published in Science Immunology, researchers from the University of Manchester posed an intriguing question: does this regulation happen via direct sensing of nutrient levels by the immune system, or does it require signaling from the brain? If the latter is the case, can these effects be induced without fasting, solely by neuronal stimulation?
Mind over body
Hunger and satiety are known to be regulated by two distinct subsets of hypothalamic neurons. The first subpopulation, called Agouti-related peptide (AgRP) neurons, promotes the feeling of hunger, while the second one, pro-opiomelanocortin (POMC) neurons, signals satiety.
The researchers genetically engineered mice in order to allow transient activation of these two groups of neurons. When AgRP neurons were activated in mice that had not fasted, the levels of circulating pro-inflammatory monocytes decreased, mirroring the effect of a 20-hour fast (a 4-hour fast did not have that effect). However, unlike in fasting, no drop in blood glucose was detected.
When fasted mice were re-fed, concurrent artificial activation of AgRP neurons prevented the expected monocyte increase, even though feeding restored normal blood glucose levels. This suggests that the brain’s perceived hunger state, driven by AgRP neurons’ activity, can override the systemic nutrient signal in regulating monocyte abundance.
In another experiment, the researchers activated satiety-promoting POMC neurons in fasted mice. This effectively reversed the fasting effect, increasing the number of monocytes despite the continuing absence of food.
“Our perceptions can shape our bodies in ways we don’t always notice. It’s easy to see how thoughts guide our actions, but this study reminds us that even our internal body adjustments that are not under conscious control respond to the brain’s signals,” said the lead senior researcher and coordinator of the study, Dr. Giuseppe D’Agostino. “This study underlines how important the brain is in regulating the immune system. But if internal or external factors alter the brain’s perception, these processes can go awry, reminding us how deeply the mind and body are – and should remain – connected.”
Collaborator and Manchester immunologist Professor Matt Hepworth added, “This work challenges the long-standing view that fasting’s immunological impact is driven purely by nutrient levels. It highlights the nervous system’s profound influence on how the immune system adapts during fasting.”
The mTOR connection
Activating AgRP neurons mimicked fasting in yet another aspect: by reducing the levels of CCL2, a cytokine known to recruit monocytes from the bone marrow into circulation. Adding exogenous CCL2 partially counteracted this effect.
Since the liver is known to regulate CCL2 levels, the researchers investigated this organ’s potential role. Interestingly, key genes that are usually upregulated in the liver during fasting were not upregulated by activating AgRP neurons. However, the researchers noticed reduced levels of hepatic mTOR activity in what resembled natural fasting. This protein, the mammalian target of rapamycin, is recognized as a potent regulator of longevity in various animal models [4].
Preventing the inhibition of mTOR in the liver blunted the effect of AgRP neuron activation on CCL2 levels and monocyte numbers. “Together, these findings suggest that hepatic mTOR activity is under direct neuronal control via hypothalamic AgRP and POMC neurons and that this control is not exclusively dependent on local nutrient availability,” the paper says.
The mechanism the researchers discovered resembles “fly-by-wire,” as opposed to a direct mechanical connection: a signal goes into the nervous system, which sends outgoing signals that eventually affect the immune system. The authors suggest that their findings might be important in the context of infections, malnutrition, and muscle wasting in cancer (cachexia).
The study’s lead author, Dr. Cavalcanti de Albuquerque, said, “By showing how the brain exerts top-down control over immune cells, we can further explore when and how fasting might deliver health benefits. It also opens up potential ways to treat infectious, inflammatory, metabolic, and psychiatric conditions.”
Literature
[1] Hunter, J., Domingues, R. G., Harno, E., Worth, A. A., Liguori, F. M., Aviello, G., Bechtold, D., White, A., Luckman, S. M., & Hepworth, M. R. (2025). Brain sensing of metabolic state regulates circulating monocytes. Science Immunology.
[2] Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., … & Belsky, D. W. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging, 3(3), 248-257.
[3] Sebastian, S. A., Shah, Y., & Arsene, C. (2024). Intermittent fasting and cardiovascular disease: A scoping review of the evidence. Disease-a-Month, 101778.
[4] Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., … & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell, 13(3), 468-477.
